Selectivity Challenges in Docking Screens for GPCR Targets and Anti-Targets.

To investigate large library docking's ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D-2 and serotonin 5-HT2A receptors were targeted, seeking selectivity against the histamine H-1 receptor. In a second campaign, x-opioid receptor ligands were sought with selectivity versus the mu-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D-2/5-HT2A ligand with 21-fold selectivity versus the H-1 receptor, this was the exception. Whereas false negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field.